Aromatic thiosemicarbazones



Patented Jan. 26, 1954 UNITED STATES PATENT OFFICE AROMATIC THIOSEMICARBAZONES "Hans Schmidt, Wuppertal-Vohwinkehiand'Robert Behnisch and Fritz Mietzsch,WuppertaFElberfeld, Germany, assignorsto "Se'henley Industries, Inc., New .York, N. Y.,- a corporation of Delaware No Drawing. .Application'August 8, 1951, Serial No. 240,978

6 Claims. (Cl. 260-152) vention'are benzalthiosemicarbazones having, as

substituents in the ortho, meta 01' para positions of the ,benzal moiety, .ialkenyloxy :or ;:alkynyloxy 1 groups. having atrmostiour carbonratoms. ,I-he

invention :also; includes ,an alpha-omegaebis oxybenzalthiosemicarbazido-alkenylene wherein the alkenylene group. is symmetrical withrespect to .the double bond. These-tcompoundsam addition to being "valuable chemo-therapeutic agents :because of their tuberculostatic properties, also possess anti-inflammatory activity and are 130- tent agents for-useinvthe treatment of leprosy.

The-compoundsgofpthis invention can be readily prepared by reacting an alkenyl or alkynyl halide .with a .hydroxy wbenzaldehyde, .wherein the hydroxy group may be in any of the three positions at choice, whereby an 'alkenyloxy or alkynyloxy substituted benzaldehyde is obtained that can be reacted .withsthiosemicarbazide to obtain theadesiredfinalproduct. If desired-, the same .final products .may .be :obtained by .treatment of functional derivatives of the corresponding aldehydes,suchsas thealdehyde oximes or hydrazones.

This application is a continuationeimpartxdf "co-pending application Serial No. 117,946, filed September 26, 1949, now abandoned, by the same inventors and entitled Thiosemicarbazones.

To facilitate a better understanding of the sub ject matter of this invention and the details of procedure whereby the products of the inventlon may be produced, certain examples herewith follow wherein the preparation of specific compounds is described but it is clearly to be understood that these examples are provided by way of illustration merely, and are not to be construed as imposing limitations upon the scope of the invention defined by the subjoined claims.

Example 1 Approximately 162 g. of 4-allyloxy-benzalde :hyde sand :91 5g. "ofthiosemicarbazide are refluxed finthreeliterscf ethanol to whichra fewdrops'ef glacial .acetic acid have been added. vThe solid :material is :gradually dissolved and ;the;boi1ing is continued .for several :hours thereafter. .-.Qn cooling, 4-allyloxyebenzalthiosemicarbazone separates as nearly colorless crystals in a good yield. "Thesecrystalsgwhich have a melting:- point of 160 C., are insoluble in-water, but a're soluble in hot ethanol and in hot 2 N caustic soda solution. On adding -lea'd acetate to an aqueous causticsoda solution of the crystals "and boiling said solution, *a precipitate forms which graduallybecomes grey.

-Emampleazz v vAbout 2012 5g. of "3eallyll=allyloxy benzaltle- .hyde andgtl g. ofthiosemicarbazide arere'fiuxed for *several hours in .250 "cc; of ethanol to which a few drops "o'f g'lacial-acetic'acid have "beerradde'd. "On cooling, colorless crystals o'f -3-allyl-4 -allyloxy benzalthiosemicarbazone separate from the clear solution. This product melts at approximately 169 C. and is'insoluble'inwater but soluble in hot ethanol.

Example 3 Approximately 17.6 g. of l-crotyloxy-benzaldehyde (which may be obtained by heating 4--hy- -droxy-.benzaldehydewith :crotylrbromide and potasslum carbonate; its boi1ing=point eat .a pressure of 4 mm. of mercury is -137" C'.) are refiuxed for several hours with 9.1 g. of thiosemi- .carbazide :in :about 301) ace. of ethanol :.-to which a-,few;drops:of;glacialiaceticzacidz'haveibeen'added.

.-At first the :solution I is clear, 'butlater the reaction eproduct crystallizes from the i hot :reaction mixture. 'llhe 14-crotyloxy-benzalthicsemicarba- .zone is ;.recovered :and za'fter :being dried, iiS :ob-

tained as a colorless, crystalline powder, melting at about C., which is insoluble in water but soluble in hot ethanol.

Example 4 About 162 g. of 3-allyloxy-benzaldehyde (which may be obtained by heating 3-hydroxybenza1dehyde with allyl bromide and potassium carbonate in ethanol solution; its boiling point at a pressure of 13 mm. of mercury is 131-134 C.) are refluxed in 1.2 liters of ethanol with 91 g. of thiosemicarbazide. When the reaction has stopped, 3-allyloxy-benzalthiosemicarbazone may be recovered therefrom in good yield as a colorless pow,- der, having a melting point of 147C. which is insoluble in water but soluble in hot ethanol. It

3 also may be dissolved by heating in a 2 N sodium hydroxide solution, and, upon addition of some lead acetate to this solution, followed by boiling, a precipitate is obtained which gradually becomes grey.

Example Approximately 17.6 g. of 3-crotyloxybenzaldehyde (which may be obtained by heating 3-hydroxybenzaldehyde with crotyl bromide and potassium carbonate in ethanol solution; its boiling point at a pressure of 4 mm. of mercury is 120121 C.) are refluxed for several hours with 9.1 g. of thiosemicarbazide in 300 cc. of ethanol,

to which a few drops of glacial acetic acid, advantageously has been-added. The 3crotyloxybenzalthiosemicarbazone, which crystallizes on cooling the reaction mixture, is recovered, dried and is thus obtained as a. colorless, crystalline powder, melting at 152 0., which is insoluble'in water but which is soluble in hot ethanol.

' Example 6 About 20.6 g. of 1:4-bis(4-formyl-phenoxy)- sym-butenylene, represented by the formula:

onoO-o-om-crecn-cm-oGcno 'is removed and washed with ethanol, is symbutenylene 1 :4-bis (4'-oxybenzalthiosemicarbazone), which may be represented by the formula:

It is a weakly colored, water-insoluble powder, melting above 270 C. with decomposition.

Example 7 Approximately 32 g. of 4-propargyloxy-benzal dehyde, which may be obtained by heating propargyl bromide with p-hydroxybenzaldehyde and potassium hydroxide in dry ethanol, M. P. 85 0., are refluxed with 18.2 g. of thiosemicarbazide in 250 cc. of ethanol. After the reaction is completed, the mixture is cooled and the crystals which have precipitated are recovered. They have a melting point of about 191 C.

Having thus described the subject matter of this invention, what it is desired to secure by Letters Patent is:

1. As a novel chemotherapeutic agent a member of the class consisting of compounds having one of the formulae wherein R is a member of the group consisting of the alkenyl and alkynyl radicals containing at most 4 carbon atoms; X is a member of the group consisting of hydrogen and alkenyl of 3 carbon atoms; and R1 is the alkenylene radical of 4 carbon atoms.

2. A chemotherapeutic agent as defined in claim 1, Formula A, wherein the OR'substituent is allyloxy in the para position and the X is hydrogen.

3. A chemotherapeutic agent as defined in claim 1, Formula A, wherein the OR substituent is crotyloxy in the para position and the X is hydrogen. V I

4. A chemotherapeutic agent as defined in claim 1, Formula A, wherein the OR substituent is allyloxy in the meta position and the X is hydrogen- 7 7 5. A chemotherapeutic agent as defined in claim 1, Formula A, wherein the OR substituent is propargyloxy in the para position and the is hydrogen. 1

6. A chemotherapeutic agent as defined claim 1, Formula B, wherein the 'R1-radical-i's the butenylene radical, CHz-CH:CHCI-Iz'.

HANS SCHMIDT. ROBERT BEHNISCH. FRITZ MIETZSCl-I.

References Cited in the file of this patent FOREIGN PATENTS iOTI-IER REFERENCES Bernstein et al., J. Am. Chem. Soc.,""vol. 73, March 1951, p. 907. m 

1. AS A NOVEL CHEMOTHERAPEUTIC AGENT A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS HAVING ONE OF THE FORMULAE 